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US20220062244A1 - APPLICATION OF MONOCYCLIC ß-LACTAM COMPOUND IN PHARMACY - Google Patents

APPLICATION OF MONOCYCLIC ß-LACTAM COMPOUND IN PHARMACY Download PDF

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US20220062244A1
US20220062244A1 US17/414,491 US201917414491A US2022062244A1 US 20220062244 A1 US20220062244 A1 US 20220062244A1 US 201917414491 A US201917414491 A US 201917414491A US 2022062244 A1 US2022062244 A1 US 2022062244A1
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Xiawei WEI
Charles Z. Ding
Jian Li
Shuhui Chen
Yuquan Wei
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Shenzhen Optimum Biological Technology Co Ltd
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Medshine Discovery Inc
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Assigned to MEDSHINE DISCOVERY INC. reassignment MEDSHINE DISCOVERY INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHEN, SHUHUI, DING, CHARLES Z., LI, JIAN, WEI, Xiawei, WEI, YUQUAN
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Assigned to Shenzhen Optimum Biological Technology Co., Ltd reassignment Shenzhen Optimum Biological Technology Co., Ltd ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MEDSHINE DISCOVERY INC.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to an application of a compound represented by formula (I) and pharmaceutically acceptable salts thereof in the field of pharmacy.
  • Antibiotic resistance kills an estimated 700,000 people each year worldwide, and some experts predict that number to reach 10 million by 2050 if efforts are not made to develop new therapeutics or therapeutic schedules (Nature, 2017, 543, 15).
  • the treatment options available for infections caused by multidrug-resistant Gram-negative bacteria, including Enterobacteriaceae and non-fermenters, are particularly limited; even more serious, the development pipeline of the pharmaceutical industry contains few compounds that can break through the resistance of bacteria (Clin. Inf. Dis., 2009, 48, 1-12).
  • AiCuris (WO 2013110643) and Novartis (WO 2015148379) reported studies to enhance activity by modifying substituents on Aztreonam molecules, respectively, with compounds of the formula shown below, wherein group A is an aromatic ring structure to which amidino and guanidino groups are attached.
  • Novartis (WO 2017050218) also reports salt forms of one of the compounds, which are currently in preclinical or clinical development.
  • the pneumonia in the application as described above is caused by infection with Pseudomonas aeruginosa.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients and/or pharmaceutically acceptable carriers.
  • the surface stabilizer in the composition as described above comprises an amphoteric surfactant, a nonionic surfactant, a cationic surfactant, or an anionic surfactant, or a combination thereof.
  • compositions as described above wherein the pharmaceutical composition in the composition as described above is for oral use.
  • the pharmaceutical composition in the composition as described above is a tablet or a capsule.
  • the pharmaceutical combination in the composition as described above is in the form of an injectable formulation or an inhaled formulation.
  • the present invention provides an application of the composition as described above in manufacture of a medicament for treating pneumonia.
  • the pneumonia in the application of the composition as described above is caused by infection with Pseudomonas aeruginosa.
  • the compound provided by the present invention has good antibacterial activity on Gram-negative bacteria, and especially has remarkable antibacterial activity on Pseudomonas aeruginosa.
  • salts refers to salts of the compounds of the present invention which are prepared from the compounds having the specified substituents found in the present invention and relatively nontoxic acids or bases.
  • base addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of base in a neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts may be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydriodic acid, phosphorous acid, and the like; and organic acid salts including acids, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid and the like; also include salts of amino acids such as arginine, as well as salts of organic acids such as glucuronic acid (see Berge et al., “Pharmaceutical Salts
  • a neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating a parent compound.
  • the parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • a “pharmaceutically acceptable salt” is a derivative of a compound of the present invention in which the parent compound is modified by salifying with an acid or with a base.
  • pharmaceutically acceptable salts include, but are not limited to: basic group such as inorganic or organic acid salts of amines, acid radicals such as alkali or organic salts of carboxylic acids.
  • the pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, for example salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate radical, carbonic acid, citric acid, edetic acid, ethane disulfonic acid, ethane sulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, hydrobromic acid, hydrochloric acid, hydriodate, hydroxy, hydroxynaphthalene, 2-hydroxyethanesulfonic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, pamoic acid, pantothenic acid, phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present invention may be synthesized from the parent compound containing an acid radical or a basic group by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or an organic solvent or a mixture of both. Generally, nonaqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred.
  • the compounds provided herein exist in the form of prodrug.
  • Prodrugs of the compounds described herein are readily converted to the compounds of the present invention by chemical changes under physiological conditions.
  • prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the absolute configuration of a stereocenter is indicated by the wedge-shaped solid bonds ( ) and the wedge-shaped dashed bonds ( ), the wedge-shaped solid bonds ( ) or the wedge-shaped dashed bonds ( ) is indicated by the wavy lines ( ) and the relative configuration of the stereocenter is indicated by the solid line bonds ( ) and the dashed line bonds ( ).
  • the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, they include E, Z geometric isomers, unless otherwise specified.
  • all tautomeric forms are included within the scope of the present invention.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, ( ⁇ )- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, all such mixtures are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers as well as D and L isomers may be prepared by chiral synthesis or chiral reagents or other conventional techniques.
  • a desired enantiomer of a compound of the present invention may be prepared by asymmetric synthesis or derivatisation be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by conventional methods well known in the art, followed by recovery to obtain pure enantiomers.
  • the enantiomers and diastereomers are typically separated using chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (e.g., formation of carbamate from an amine).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds may be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • pharmaceutically acceptable carrier refers to any formulation or carrier medium capable of delivering an effective amount of an active agent of the present invention without interfering with the biological activity of the active agent and without toxic or side effects to the host or patient.
  • Representative carriers include water, oils, vegetables and minerals, creams, lotions bases, ointments bases, and the like. These include suspending agents, tackifiers, transdermal enhancers, and the like.
  • excipient generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • an “effective amount” or “therapeutically effective amount” refers to an amount of the drug or agent that is nontoxic but sufficient to achieve the desired effect.
  • an “effective amount” of one active substance in a composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition. Determination of the effective amount will vary from person to person, depending on the age and general condition of the recipient, and also on the particular active substance, and suitable effective amounts in each case may be determined by one skilled in the art according to routine experimentation.
  • active ingredient refers to a chemical entity that is effective in treating a disorder, disease, or condition of interest.
  • the solvents used in the present invention are commercially available.
  • the Present Invention Adopts the Following Abbreviations
  • FIG. 1 shows the results of the lung bacterial load in the treatment of pulmonary Pseudomonas aeruginosa infection in immunosuppressive mice.
  • Step 1 To THF (1.50 L) were added Compound A1_1 (100.00 g, 642.76 mmol, 1.00 eq) and triethylamine (136.59 g, 1.35 mol, 187.10 mL, 2.10 eq), and the resulting mixture was cooled to 0° C.; Boc 2 O (154.31 g, 707.03 mmol, 162.43 mL, 1.10 eq) in THF (500.00 mL) was added dropwise at this temperature, the reaction mixture was warmed to 10° C.
  • Step 2 A1_2 was dissolved in THF (2000 mL), the mixture was stirred at ⁇ 50° C. for 10 min, then MeMgBr (3M, 638.59 mL, 6.00 eq) was added dropwise over 20 min at ⁇ 50° C. The resulting mixture was stirred at 25° C. for 60 min before the reaction mixture was quenched at 0° C.
  • Step 3 A1_3 (30 g, 136.81 mmol, 1.00 eq) was dissolved in a mixed solution of sodium phosphate buffer (540.00 mL, 0.7 M, 2.76 eq) and acetonitrile (300 mL), then TEMPO (2.15 g, 13.68 mmol, 0.10 eq) was added, NaClO (81.47 g, 5.47 mmol, 67.33 mL, purity 0.5%, 0.04 eq) and NaClO 2 (98.99 g, 1.09 mol, 8.00 eq) in water (300 mL) were added dropwise by stirring at 35° C.; the resulting mixture was stirred at 35° C.
  • Step 4 A1_4 (48 g, 205.78 mmol, 1.00 eq) was dissolved in DMF (700 mL), then DCC (84.92 g, 411.56 mmol, 83.25 mL, 2.00 eq) and HOBt (55.61 g, 411.56 mmol, 2 eq) were added, the mixture was stirred at 10° C.
  • Step 5 A1_5 (57 g, 168.44 mmol, 1 eq) was dissolved in pyridine (600 mL) by stirring at 55° C. for 12 h, and sulfur trioxide pyridine (187.67 g, 1.18 mol, 7 eq) was added; the reaction mixture was then concentrated under reduced pressure and the resulting solid was dissolved in ethyl acetate (800 mL); to the solid was added aqueous potassium carbonate (816.94 mL, 2 M, 9.7 eq) dropwise at 0° C. and the resulting mixture was stirred at 100° C.
  • Step 6 A1_6 (31 g, 96.76 mmol, 1.00 eq) was dissolved in methanol (620 mL) and Pd/C (3 g, 10%) was added under a nitrogen atmosphere, then the reaction vial was replaced with nitrogen three times, then the reaction vial was charged with hydrogen gas at 20° C. and reacted under 50 psi atmosphere for 1 h, then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to obtain Compound A1_7.
  • Step 7 to a solution of A1_7 (22 g, 95.54 mmol, 1.00 eq) in DMF (220 mL) was added DMF.SO 3 (17.56 g, 114.65 mmol, 1.2 eq); the mixture was stirred at 0° C.
  • Step 8 A1_8 (68 g, 123.24 mmol, 1.00 eq) was added to trifluoroacetic acid (300 mL) and the mixture was stirred at 15° C. for 4 h under a nitrogen atmosphere; the reaction mixture was diluted with dichloromethane (350 mL) and filtered, and the filtrate was concentrated under reduced pressure to obtain Compound A1.
  • Step 1 to a solution of A2_1 (7 g, 53.35 mmol, 7.54 mL, 1 eq) in THF (70 mL) was slowly dropwise added BOC-ONB (29.80 g, 106.69 mmol, 2 eq) and Et 3 N (11.34 g, 112.03 mmol, 15.59 mL, 2.1 eq) in THF (330 mL) at 20° C., and the resulting mixture was stirred at 20° C.
  • BOC-ONB 29.80 g, 106.69 mmol, 2 eq
  • Et 3 N 11.34 g, 112.03 mmol, 15.59 mL, 2.1 eq
  • Step 3 Compound A2_3 (4.2 g, 11.78 mmol, 1 eq) and pyrazole hydrochloride (1.23 g, 11.78 mmol, 1 eq) were added to THF (40 mL) and replaced with nitrogen three times, then the mixture was stirred at 75° C. for 12 h; the reaction was cooled to room temperature, diluted with ethyl acetate (100 mL), filtered and the filter cake was collected to obtain Compound A2_4 after drying.
  • Step 4 to a solution of Compound A2_4 (2.1 g, 4.56 mmol, 1 eq) in DCM (20 mL) at 0° C. was added TFAA (765.41 mg, 3.64 mmol, 506.89 ⁇ L, 0.8 eq) and triethylamine (1.01 g, 10.02 mmol, 1.39 mL, 2.2 eq), the mixture was stirred at 0° C. for 20 min then diluted with water (20 mL), the resulting mixture was extracted with DCM (50 mL*2), the organic layers were combined and concentrated under reduced pressure to obtain Compound A2.
  • Step 1 Compound A3_1 was added to a mixed solution of 1,1,1,3,3,3-hexafluoro-2-(trifluoromethyl) propan-2-ol (10.16 g, 43.06 mmol, 10 eq) and DCM (20 mL), the reactant was stirred at room temperature for 45 min (20-25° C.) and concentrated under reduced pressure to obtain Compound A3.
  • Step 1 to a solution of compound 1_1 (29 g, 128.30 mmol, 1 eq) in THF (300 mL) was added BH 3 .SMe 2 (10 M, 38.49 mL, 3 eq). The mixture was reacted at 80° C. for 12 h, then cooled to 0° C., and quenched with methanol (100 mL); diluted hydrochloric acid (90 mL, 1 M) was then added by stirring at 80° C.
  • Step 2 to a solution of compound 1_2 (6 g, 30.29 mmol, 1 eq) in dichloromethane (50 mL) was added Boc 2 O (6.61 g, 30.29 mmol, 6.96 mL, 1 eq) and triethylamine (6.13 g, 60.59 mmol, 8.43 mL, 2 eq); the mixture was stirred at 20° C.
  • Step 3 to Compound 1_3 (9 g, 30.18 mmol, 1 eq) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bis (1,3,2-dioxaborane) (15.33 g, 60.37 mmol, 2 eq) in DMSO (150 mL) was added Pd(dppf)Cl 2 .CH 2 Cl 2 (2.46 g, 3.02 mmol, 0.1 eq) and potassium acetate (11.85 g, 120.73 mmol, 4 eq); the mixture was replaced with nitrogen three times and stirred at 90° C.
  • Step 4 to a solution of Compound 1_4 (11 g, 31.86 mmol, 1 eq) in THF (100 mL) was added H 2 O 2 (86.69 g, 764.69 mmol, 73.47 mL, purity 30%, 24 eq) and acetic acid (9.95 g, 165.68 mmol, 9.48 mL, 5.2 eq); the mixture was stirred at 20° C.
  • Step 5 to a solution of Intermediate 1_5 (6.8 g, 26.69 mmol, 1 eq), ethyl oxirane-2-carboxylate (7.75 g, 66.72 mmol, 2.5 eq), and 4 ⁇ molecular sieves (8 g) in MTBE (10 mL) was added Catalyst A3 (673.34 mg, 800.64 ⁇ mol, 0.03 eq), the mixture was replaced with nitrogen three times and stirred at 20° C.
  • Step 6 to a solution of compound 1_6 (6.3 g, 17.32 mmol, 1 eq) in DCM (20 mL) was added TFA (14.88 g, 130.51 mmol, 9.66 mL, 7.53 eq) at 0° C., the mixture was stirred at 20° C. for 1 h and concentrated under reduced pressure to obtain trifluoroacetic acid salt of Compound 1_7.
  • Step 7 to a solution of Intermediate A2 (3.8 g, 7.30 mmol, 1 eq) in DMF (30 mL) was added triethylamine (2.95 g, 29.20 mmol, 4.06 mL, 4 eq) and trifluoroacetic acid salt of Compound 1_7 (5.33 g, 14.60 mmol, 2 eq); the mixture was stirred at 45° C.
  • Step 9 to a solution of Compound 1_9 (2 g, 3.45 mmol, 1 eq) in MeOH (20 mL) was added diphenyldiazomethane (1.34 g, 6.90 mmol, 2 eq); the mixture was stirred at 20° C.
  • Step 10 to a solution of Compound 1_10 (1.2 g, 1.42 mmol, 1 eq) and 2-hydroxyisoindoline-1,3-dione (278.65 mg, 1.71 mmol, 1.2 eq) in THF (12 mL) was added PPh 3 (560.04 mg, 2.14 mmol, 1.5 eq) and DIAD (431.75 mg, 2.14 mmol, 415.15 ⁇ L, 1.5 eq) at 0° C.; the mixture was stirred at 20° C.
  • Step 11 to a solution of Compound 1_11 (1 g, 1.10 mmol, 1 eq) in EtOH (10 mL) was added NH 2 NH 2 .H 2 O (77.95 mg, 1.32 mmol, 75.68 ⁇ L, purity 85%, 1.2 eq); the mixture was stirred at 20° C. for 30 min, filtered and the filtrate was concentrated under reduced pressure, the residue was diluted with water (10 mL) and extracted with DCM (20 mL), the combined organic layers were dried over anhydrous ammonium sulfate, filtered and concentrated under reduced pressure to obtain Compound 1_12.
  • Step 13 to a solution of Compound 1_13 (200 mg, 163.39 ⁇ mol, 1 eq) in DMF (2 mL) was added N,N-diisopropylcarbodiimide (41.24 mg, 326.77 ⁇ mol, 2 eq) and HOBt (44.15 mg, 326.77 ⁇ mol, 2 eq); after the mixture was stirred at 20° C. for 1 h, Intermediate A1 (48.08 mg, 228.74 ⁇ mol, 1.4 eq) and NaHCO 3 (54.90 mg, 653.55 ⁇ mol, 25.42 ⁇ L, 4 eq) were added and stirred at 20° C. for 11 h; the reaction mixture was diluted with water (8 mL), and the solid was collected by filtration to obtain Compound 1_14.
  • Step 14 to a solution of Compound 1_14 (220 mg, 163.01 ⁇ mol, 1 eq) in DCM (1 mL) was added TFA (1.54 g, 13.51 mmol, 1 mL, 82.85 eq) at 0° C.
  • Pseudomonas aeruginosa PA14 Pseudomonas aeruginosa PA14.
  • Test compound A compound represented by formula (I),
  • Reference compound AiCuris patent WO 2018065636 reference compound I-g, aztreonam (product of Dalian Meilunbio Biotechnology Co., Ltd.).
  • MHA Mueller-Hinton agar
  • TSA medium purchased from BD.
  • mice 46 immunosuppressive mice were formed by intraperitoneal injection of cyclophosphamide 150 mg/kg on day 1 and day 4.
  • Seven groups were set up, including high, medium and low dose groups of compound represented by formula (I), high and medium-dose groups of compound I-g, aztreonam group and model group; there were 6 animals in each group, the other 4 animals were subjected to pulmonary infection for 2 h, and the lung tissues were removed to count the bacterial load. See the table below for specific grouping.
  • mice were injected intratracheally with 50 ⁇ L of bacterial fluid (2 ⁇ 10 3 CFU). Four model mice were sacrificed 2 h after infection.
  • mice were injected intraperitoneally once at 2 h, 4 h, 6 h and 8 h according to the groups, for a total of 4 times.
  • mice in each group were sacrificed by cervical dislocation, and the lung and kidney tissues were removed aseptically, then placed into sterilized homogenate tube, weighed, added with proper amount of normal saline (NS), and homogenized by a homogenizer for 1 min; the lung tissues in model group were diluted 10 4 , 10 5 , and 10 6 -fold, the lung tissues in each administration group were diluted 10 and 100-fold, the kidney tissues in model group were diluted 10 2 , 10 3 , and 10 4 -fold, and the lung tissues in each administration group were diluted 10-fold; the serial diluents were plated onto TSA plates with a spiral coater, and incubated overnight at 37° C. to determine CFU counts with a colony counter.
  • NS normal saline
  • mice were weighed each day after the start of the test and body weight changes were recorded.
  • CFU scatter plots of lung tissue were made using Graphpad Prism mapping software.
  • the average CFU and body weight were calculated by SPSS 19.0 software, and the differences between groups were analyzed by variance analysis.
  • mice injected with cyclophosphamide twice intraperitoneally were infected with Pseudomonas aeruginosa PA14 about 1.06 ⁇ 10 4 CFU; after 2 h, the lung tissues were removed and homogenated to determine bacteria counting; bacterial load in mice was calculated, with average load ranging from 5.10 ⁇ 10 3 CFU.
  • mice were injected intraperitoneally with compounds of formula (I), compound I-g and aztreonam at 2 h, 4 h, 6 h and 8 h after infection; animals were sacrificed at 24 h, lung tissues were removed aseptically, immersed in normal saline (NS), homogenized, diluted appropriately, and then 50 ⁇ L of diluents were evenly plated onto TSA plates; the plates were incubated overnight in a 37° C. incubator to count the number of colonies, which was converted to CFU per milliliter by a dilution ratio, and logarithmic value of the bacterial load was calculated of base 10, and the mean and standard deviation were compared in each group. The results were shown in Table 3 and FIG. 1 .
  • the bacterial load at 24 h in the model group increased from 1.06 ⁇ 10 4 CFU to 3.34 ⁇ 10 8 CFU (LOG 10 of the bacterial load was 8.14).
  • the bacterial load of each administration group was significantly lower than that of the model group, and was basically eliminated.
  • the compound represented by formula (I) was completely eliminated in the high, middle and low-dose groups.
  • the compound represented by formula (I) has in vivo curative effect on pulmonary Pseudomonas aeruginosa infection in immunosuppressed mice caused by cyclophosphamide, and may remarkably reduce the bacterial load of lung tissues and eliminate Pseudomonas aeruginosa infected on the lung. Wherein the compound represented by formula (I) completely eliminated the bacteria infected on the lung at the lowest dose. The body weight of the animals in the administration group was not significantly changed, indicating that the compound represented by formula (I) is safe.

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CN113227088B (zh) 2022-05-31
EP3901150A4 (en) 2022-09-07
EP3901150A1 (en) 2021-10-27
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